The long range goal of this project is to develop effective topical microbicides for prevention of sexually transmitted HIV infection. In the proposed studies we will determine the virucidal activity of a series of porphyrin and metalloporphyrin compounds against infectious HIV- l and SIV virions. Based on results of our initial studies, Project l will design additional novel porphyrin compounds which will be evaluated in this project for their virucidal activity vs. HIV virions. The kinetics of inactivation as well as the possible pH-dependence of the virucidal effect will be determined against several HIV- l isolates, including primary isolates of subtypes A, C, and E. which are epidemiologicaIly most likely to be involved in sexual transmission. We will also evaluate the ability of the active compounds to protect cell cultures against infection by HIV or SIV. We will investigate alternative possible mechanisms by which these compounds could inactivate virion infectivity, including binding to specific viral proteins, disruptive effects on the structural integrity of the virion, and effects on specific functional activates of viral proteins. Because HIV has a high mutation rate, sequence variation in structural proteins might conceivably confer resistance to a given compound, depending on its mechanism of action. If such resistant mutants are detected, we will map the genetic alteration which is responsible, and determine whether any viral variants which are found to exhibit resistance to a specific compound will also exhibit resistance to other virucidal porphyrin compounds with distinct structural features. In preliminary studies, we have demonstrated that cell-free SIV can initiate infection following inoculation into the genital tract of female rhesus macaques. Based on the results of assays for virucidal activity obtained in this project and studies of the effects of porphyrins upon reproductive physiology in Project 5, the virucidal porphyrins which are most effective in cell culture systems and have no undesirable effects on physiology of the reproductive tract will be used in a primate model to determine the ability of pretreatment of the genital tract with these compounds to confer protection against challenge with infectious, pathogenic SIV. Thus. the project will develop a novel class of rnicrobicidal compounds, which are also active against sexually transmitted bacteria and herpesvirus.